Altered Gemcitabine and Nab-paclitaxel Scheduling Improves Therapeutic Efficacy Compared with Standard Concurrent Treatment in Preclinical Models of Pancreatic Cancer

Clin Cancer Res. 2021 Jan 15;27(2):554-565. doi: 10.1158/1078-0432.CCR-20-1422. Epub 2020 Oct 21.


Purpose: Concurrent gemcitabine and nab-paclitaxel treatment is one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). Previous studies demonstrate that caveolin-1 (Cav-1) expression is critical for nab-paclitaxel uptake into tumors and correlates with response. Gemcitabine increases nab-paclitaxel uptake by increasing Cav-1 expression. Thus, we hypothesized that pretreatment with gemcitabine would further enhance the sensitivity of PDAC to nab-paclitaxel by increasing Cav-1 expression and nab-paclitaxel uptake.

Experimental design: We investigated the sensitivity of different gemcitabine and nab-paclitaxel treatment regimens in a panel of PDAC cell lines and orthotopic xenograft models. The sensitivity of different treatment regimens was compared with the standard concurrent treatment.

Results: Pretreatment with gemcitabine before nab-paclitaxel increased Cav-1 and albumin uptake and significantly decreased proliferation and clonogenicity compared with concurrent treatment, which correlated with increased levels of apoptosis. Cav-1 silencing reduced the uptake of albumin, and therapeutic advantage was observed when cells were pretreated with gemcitabine prior to nab-paclitaxel. In addition, we observed that pretreatment with gemcitabine resulted in partial synchronization of cells in the G2-M-phase at the time of nab-paclitaxel treatment, providing another mechanism for the benefit of altered scheduling. In heterotopic and orthotopic xenograft models, the altered schedule of gemcitabine prior to nab-paclitaxel significantly delayed tumor growth compared with concurrent delivery without added toxicity.

Conclusions: Pretreatment with gemcitabine significantly increased nab-paclitaxel uptake and correlated with an increased treatment efficacy and survival benefit in preclinical models, compared with standard concurrent treatment. These results justify preclinical and clinical testing of this altered scheduling combination.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / administration & dosage
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Administration Schedule
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Nude
  • Mice, SCID
  • Paclitaxel / administration & dosage
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Treatment Outcome
  • Tumor Burden / drug effects*
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays / methods*


  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Caveolin 1
  • Deoxycytidine
  • Paclitaxel
  • Gemcitabine